Progress in the study of novel small molecule mechanism of inter-fungal communication activation

The living environment of fungi is complex.
In nature, the coexistence of fungi and bacteria, plants, animals and even humans is common
.

The rich species diversity and the changeable living environment have caused fungi to evolve a unique set of mechanisms to respond to the environment and communicate with the organisms in the environment
.

This communication and response to nature prompts fungi to produce active secondary metabolites with novel, complex and diverse types of structures, and provide abundant resources for new drug discovery
.

However, how fungi communicate with microbes in the environment and the molecular and biochemical mechanisms remain unclear
.

Yin Wenbing's research group, Institute of Microbiology, Chinese Academy of Sciences, is devoted to the study of gene regulation mechanism and function of fungal secondary metabolites
.

Recently, in the study of the interaction between the model fungus Aspergillus nidulans and other fungi, the research group screened out an endophytic fungus Epicoccum dendrobii, which caused global changes in the secondary metabolic profile of Aspergillus nidulans ( Figure 1)
.

Further research found that during the co-cultivation process, Dendrobium can induce significant changes in fungal secondary metabolites of at least 4 genera (Fig.
1), indicating that this bacterium as a donor bacterium has a universal mechanism to stimulate the recipient bacterium.
, and the recipient bacteria respond by regulating changes in secondary metabolism, resulting in the production of some new secondary metabolites (Fig.
1)
.

 　　However, how is this response achieved? Taking the co-culture system of Aspergillus nidulans and Dendrobium as a model, Yin Wenbing's research group analyzed its response mechanism from the aspects of biology, chemistry and genetics
.

Transcriptomic and metabolomic analysis showed that 15.
4% of genes in Aspergillus nidulans were significantly up-regulated, 19% were significantly down-regulated, 22 secondary metabolite yields were significantly increased, and 8 new structures of polyketides were identified Aspernidines (Figure 1)
.

Transcriptome data analysis combined with gene knockout and complementation experiments demonstrated that the key regulatory element in A.
nidulans responding to stimuli is the allelic protein of the global regulator VeA-VeA1 protein (deletion of the first 36 amino acids of VeA), and It is involved in regulation in coordination with LaeA and VelB in the Velvet complex (Fig.
2)
.

The study further found that the downstream transcription factor SclB is regulated by the VeA1 protein and is involved in the regulation and activation of multiple biosynthetic gene clusters such as Aspernidines, revealing a complex gene regulatory network (Figure 2)
.

At the same time, this regulatory network was also validated in Aspergillus fumigatus
.

 　　This study is the first to propose the metabolic regulatory function of the partially-deficient VeA1 protein, revealing that the co-culture between fungi is mediated by VeA1, through the LaeA-VeA1-VelB complex, and then through the complex response regulatory network of the downstream transcription factor SclB (Fig.
2), which provides a solid theoretical basis for the study of the regulation mechanism of fungi-fungi co-culture, which is a preliminary exploration of the response and communication mechanism under the coexistence of fungi and multiple species in nature, and also provides a basis for the development of new natural products.
an effective strategy
.

 　　Relevant research results are published in Science Advances in the form of a research article (Article), titled Fungal-fungal cocultivation leads to widespread secondary metabolite alteration requiring the partial loss-of-function VeA1 protein
.

The research work is supported by the National Key R&D Program, the National Natural Science Foundation of China, the "From 0 to 1" Original Innovation Project of the Basic Frontier Scientific Research Program of the Chinese Academy of Sciences, the Strategic Biological Resource Program of the Chinese Academy of Sciences, and the Postdoctoral Science Fund
.

  Figure 1.
The universal co-culture system induced by the donor bacterium Dendrobium E.
nidulans (A and B); the global transcriptome and metabolome changes induced by the co-culture of D.
dendrobii E.
nidulans and Aspergillus nidulans, the serial number marked in red is the new structure ( C and D) Figure 2.
Schematic diagram of the regulation mechanism of global changes in secondary metabolites under fungal-fungus co-culture conditions Source: Institute of Microbiology, Chinese Academy of Sciences